Discussed Poster Abstracts
Fundamental & Clinical Pharmacology
ES SESSION DE POSTERS MODER PHARMACOLOGIE CLINIQUE PM2-001 Screening for phenotypical variation in CYP activity in patients with therapeutic problem in psychiatric settings C Lloret-Linaresa, V Rollasonb, R Ingb, C Samerb, Y Daalib, M Rebsamenb, J Desmeulesb, M Bessonb aINSERM U1144, Variability of the response to psychotropic drugs, Paris Descartes University and Paris Diderot University, Paris75005, France – Paris (France); bService de Pharmacologie et Toxicologie Cliniques H^opitaux Universitaires de Geneve (HUG) – Geneve (Switzerland) Introduction: This retrospective study aimed to assess how much the assessment of CYP activity recommended by clinical pharmacologist of the Geneva University hospitals allowed to explain therapeutic problems in patients on psychotropic agents. Material and methods: We collected the results of the genetic and phenotypic investigations that were performed from 2005 until November 2014 in patients receiving psychotropic drugs as well as their indication. The link between CYP activities and the clinical or biological event (side effects/ resistance/low or high concentrations) was determined independently by two clinical pharmacologists according to a semi-quantitative scale: 0 = no or weak probability of link; 1 = intermediate probability of link; 2 = high probability of link. In case of disagreement, a third clinical pharmacologist scored the link. Results: Among the 695 pharmacological advices involving metabolic exploration (CYP phenotype and/or genotype determination) during this period, 260 concerned psychotropic drugs. Among them, 135 cases included a complete statement of metabolic pathways of the drug of interest. Advices mostly concerned antidepressants (n = 90), including tricyclic antidepressants (n = 14), followed by antipsychotics (n = 27), benzodiazepines and hypnotics (n = 14), and psychostimulants (n = 4). The phenotype and/or genotype determination was performed for the following reasons: side effects (n = 73, 54.1%) lack of efficacy (n = 44, 32.6%), low concentrations (n = 14, 10.4%), high concentrations (n = 4, 3.0%). There was a good agreement between the two clinical pharmacologists, who scored the same way in 97% of cases (131/135). According to the statement of the three pharmacologists, in 22% (n = 30) and 12.6% (n = 17) of the cases, a modified activity of CYP450 explained the therapeutic problem with a high and intermediate probability, respectively. In patients with side effects, these probabilities were 22.3% and 17% respectively whereas for a lack of efficacy, they were 13.6% and 11.4% respectively. Discussion / Conclusion: This analysis showed that, when indicated by clinical pharmacologists, metabolic exploration explained clinical or biological events related to drug intake in approximately 35% of psychiatric patients. These findings should encourage more systematic assessment of metabolic pathways in these patients [1–2]. References: [1] Samer CF, L et al.. Mol Diagn Ther. 2013 Jun;17(3):165–84. Review. [2] Kirchheiner J, et al. Mol Psychiatry. 2004;9(5):442–73. PM2-002 Development of a rapid and sensitive method for simultaneous determination of imatinib and sorafenib in human plasma by LC tandem mass spectrometry – Clinical application to patients with hepatocellular carcinoma treated by sorafenib S Bodeaua, Y Bennisa, G Tueurb, L Dumontb, N Bargetc, JC Trinchetc, N Gannec, G Briccad, A Galmichee, AS Hurtel-Lemaireb aDepartment of Pharmacology – Toxicology, CHU Amiens and UMR_1088 INSERM unit, UPJV – Amiens (France); b Department of Pharmacology – Toxicology, CHU Amiens – Amiens (France); c Department of Hepatology, Hopital Jean-Verdier, APHP – Bondy (France); d Department of Clinical Pharmacology and Pharmacovigilance, CHU Amiens and UMR_1088 INSERM unit, UPJV – Amiens (France); eDepartment of Biochemistry, CHU Amiens and EA4666, UPJV – Amiens (France) Introduction: Tyrosine kinase inhibitors (TKIs) based therapies represent a new way to treat cancers. While fixed dosing is a standard practice for TKIs, there is increasing interest for Therapeutic Drug Monitoring (TDM). Indeed, there is evidence that TKIs pharmacokinetic is highly variable between individuals and that this should influence treatment outcomes. In this context, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of imatinib and sorafenib concentrations and we used it to evaluate the sorafenib through concentrations in a retrospective study conducted in 20 patients with advanced hepatocellular carcinoma (HCC). Material and methods: Twenty patients with advanced HCC treated with sorafenib (800 mg/day) between January 2012 and October 2014 in the ParisSeine-Saint-Denis University Hospitals were included. Sorafenib through concentrations were measured by a validated LC-MS/MS method in plasma samples collected 4–24 weeks after the onset of treatment with sorafenib. Chromatographic separation was performed with a kinetex C18 column using [13C, 2H3]-sorafenib as internal standard. Detection was performed with a triple quadrupole mass spectrometer that monitored two specific transitions per compound in electrospray positive-ion selected reaction monitoring mode. Results: Upon short term clinical evaluation, the disease was stable in seven patients and progressive in 13 patients. None of these 20 patients responded to sorafenib according to the Modified Response Evaluation Criteria In Solid Tumours (mRECIST). We observed a large inter individual variability for sorafenib through concentrations which ranged between 0.3 lg/mL and 26.3 lg/mL (median: 4.5 lg/mL). We also noticed a trend towards an association between the sorafenib plasma concentrations and the disease stability (2.94 lg/mL versus 7.85 lg/mL; Mann Whitney test, P = 0.13). A sorafenib through concentration of 7.015 lg/mL best discriminate the two groups in this study (ROC curve, AUC = 0.71; sensibility=0.71, specificity= 0.85). Because of the limited number of
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patients included in the analysis, such results will have to be confirmed in further studies. Discussion / Conclusion: Further research is required to determine the exact correlation between sorafenib exposure and treatment benefit. Overall, TDM presents several benefits: i) to control patients’ compliance to treatment which could explain a lack of response, ii) to prevent drug-drug interactions and iii) to prevent treatment toxicity. PM2-003 Population pharmacokinetics of mycophenolic acid in both plasma and peripheral blood mononuclear cells in adult renal transplant recipients C Baraua, C Verstuyftb, C Bazzolic, H Benechd, A Barrail-Trana, L Becquemonte, AM Tabureta, A Durrbachf, V Furlana aAssistance Publique – H^opitaux de Paris, H^opital Bic^etre, H^opitaux Universitaires Paris Sud, Service de Pharmacie Clinique – Paris (France); bAssistance Publique – H^opitaux de Paris, H^opital Bic^etre, H^opitaux Universitaires Paris Sud, Service de Genetique Moleculaire, Pharmacogenetique et Hormonologie – Paris (France); cLaboratoire Jean Kuntzmann, Universite de Grenoble et CNRS – Grenoble (France); dService de Pharmacologie et d’Immunoanalyse, CEA – Gif Sur Yvette (France); eAssistance Publique – H^opitaux de Paris, H^opital Bic^etre, H^opitaux Universitaires Paris Sud, Centre de Recherche Clinique (CRC Paris Sud) – Paris (France); fAssistance Publique – H^opitaux de Paris, H^opital Bic^etre, H^opitaux Universitaires Paris Sud, Service de Nephrologie et INSERM U542 – Paris (France) Introduction: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is widely used for the prophylaxis of rejection in renal transplantation. MPA efficacy is known to be linked to its binding to intracellular inosine monophosphate dehydrogenase (IMPDH). Owing to MPA intracellular mechanism of action, factors influencing MPA concentrations in Peripheral Blood Mononuclear Cells (PBMCs) must be fully understood. This study aimed to describe for the first time the pharmacokinetic parameters in both plasma and PBMC in adult renal transplant patients. Material and methods: Seventy-seven renal transplant recipients treated with a fixed MMF dose of 1000 mg bid were included. Total plasma and PBMC MPA concentrations were adequately described by a three-compartment model with zero-order absorption. Demographical, biological and pharmacogenetic covariates were investigated, focusing on the different genetic polymorphisms in genes involved in MPA transport, ABCB1, encoding P-glycoprotein (MDR1), ABCC2, encoding MRP2 (ABCC2), SLCO1B1, encoding OATP1B1 and SLCO1B3, encoding OATP1B3. Results: MPA concentrations in PBMCs were close to total plasma concentrations and well above half-maximal inhibition concentration for IMPDH (IC50 = 0.026 mg/L). This can be explained by uptake and efflux clearances related to PBMC compartment, which were in the same order of magnitude (21.0 and 28.9L/h respectively). Moreover, MPA concentrations in PBMC remained steady and parallel to unbound MPA in plasma throughout the 6-month follow up. In contrast, total concentrations of MPA were dependent on albumin concentrations. Interestingly, no genetic polymorphism was found to influence MPA pharmacokinetics in PBMC, but ABCB1 3435C>T SNP influenced apparent volume of distribution, suggesting that MPA could be a substrate for the ABCB1 transporter. Discussion / Conclusion: These results indicate that MPA concentrations in PBMC may not be a limiting factor for efficacy. Nevertheless, further studies are warranted to investigate whether unbound MPA concentrations or MPA concentration in PBMC could be relevant parameters to optimize dosing regimen. PM2-004 Determination of dabigatran plasma concentration using the coagulation assay STAâ-ECA II versus HPLC-MS/MS M Rousseta, K Khennoufaa, K Titiera, G Freyburgerb, M Molimarda aLaboratoire de Pharmacologie et Toxicologie, CHU Pellegrin – Bordeaux (France); bLaboratoire d’Hematologie, CHU Pellegrin – Bordeaux (France) Introduction: Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with non-valvular atrial fibrillation and for prevention and treatment of peripheral thromboembolism. Although therapeutic drug monitoring is not recommended, there may be situations in which it is required to measure plasma concentration. For this, various coagulation assays have been developed, such as the STAâ-ECA II test (Diagnostica Stago, Asnieres, France). The study presented here compares this test to high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for dabigatran measurement. Material and methods: The coagulation assay was performed on STA-Râ using the STAâ-ECA II test, which is a chromogenic method for quantitative determination of the anti-IIa activity of plasmatic dabigatran. HPLC-MS/MS: free-dabigatran concentration determination was performed using a Waters Quattro Micro detector and validated in accordance with EMEA 2012 Guidelines; total dabigatran concentration determination was performed by Nuvisan Pharma Services (Neu-Ulm, Germany) on hydrolysed samples, using an Agilent 1200 series detector. Correlation between the STAâ-ECA II test and HPLC-MS/MS methods was assessed using 88 plasma samples from treated patients. Results: For free-dabigatran, the correlation between STAâ-ECA II and HPLCMS/MS was good in the low range of dabigatran plasma concentrations (15– 150 ng/mL; r² = 0.963). Correlation was not good above 150 ng/mL (r²=0.784); dabigatran concentration was always higher when assessed by STAâ-ECA II than by HPLC-MS/MS. For total plasmatic dabigatran (free-dabigatran and dabigatran metabolite), correlation was excellent between STAâ-ECA II and HPLC MS/MS across the total range of plasma concentrations (15–460 ng/ mL; r² = 0.977). Discussion / Conclusion: The STA-ECA II test correlated with total but not free dabigatran plasma concentrations. This is attributable to the presence of the active metabolite (dabigatran acylglucuronide) in samples from treated patients, and which accounts for up to 20% of total plasma dabigatran [1–2].
© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique 29 (Suppl. 1), 34–46
Abstracts – Discussed Posters 2015
References: [1] Stangier J. et al. Br J Clin Pharmacol. 2007 64:292–303. [2] Ebner T. et al. Drug Metab Dispos. 2010 38:1567–75.
References: [1] Werner CR et al. Liver Transplantation 2012; 18: 1464–70. [2] Garg V et al. Hepatology 2011; 54: 20 – 7.
PM2-005 Drug interaction between sulfamethoxazole-trimethoprim and tacrolimus in renal transplant patients M Ben Sassi, E Gaies, O Charfi, R Charfi, N Jebabli, H El Jebari, M Lakhal, A Klouz, I Salouage, S Trabelsi Pharmacologie Clinique, Centre National de Pharmacovigilance – Tunis (Tunisia) Introduction: Tacrolimus is a calcineurin inhibitor, used as a first line immunosuppressant agent in organ transplant recipients, especially in kidney transplantation. Its therapeutic drug monitoring is essential because of the narrow therapeutic range, the pharmacokinetic inter and intra-individual variabilities and the risk of drug interactions. The infection remains a common complication in these patients. So many anti-microbial agents can interact significantly with tacrolimus as antifungal drugs and rifampicin. However, interaction with sulfamethoxazole-trimethoprim (ST) has not been described previously. Aim: To evaluate the influence of ST tacrolimus exposition to (AUC0–12 h, AUC0– 12 h/Dose) in kidney transplant patients. Material and methods: It consisted in a retrospective study made in the department of Clinical Pharmacology in renal transplant recipients treated by tacrolimus from 2011 to 2014. The samples were analyzed by an automated enzymelinked immunoassay (ARCHITECT-ABBOTT). Abbreviated AUC0–12 h using three time points at T0 h, T1 h and T3 h were measured. Therapeutic range is between 180 to 270 ng*h/mL for recent transplantation (≤1 month) and from 100 to 190 ng*h/mL for transplantation at a stable period (>1 month). Results: We had collected 59 pharmacokinetic profiles from 37 renal transplant patients. The median age was 32 years. The average weight was 64 kg. The sex ratio was 1.85. The average dose was 0.11 mg/kg/day. Among our patients, 11 had taken ST in association to tacrolimus. Table 1 Distribution of pharmacological parameters
PM2-007 Determination of Inosine Triphosphate Pyrophosphatase phenotype in red blood cells using HPLC A Citterio-Quentina, S Longb, JP Salvic, M Moulsmad, R Boulieue aUniversite Lyon 1, Faculte de Pharmacie, Pharmacie clinique et Pharmacocinetique – CHU de Lyon, GHEH, Pharmaco-Toxicologie – Lyon (France); bSchool of Pharmacy 1 – Dublin (Ireland); cUniversite Lyon 1,Faculte de Pharmacie, Pharmacie clinique et Pharmacocinetique – Lyon (France); dCHU de Lyon, GHEH, Pharmaco-Toxicologie – Lyon (France); eUniversite Lyon 1,Faculte de Pharmacie, Pharmacie clinique et Pharmacocinetique – CHU de Lyon, GHEH, Pharmacocinetique Clinique – Lyon (France) Introduction: Thiopurine drugs are well established immunosuppressive agents with proven clinical efficacy in various conditions, including inflammatory bowel disease and leukaemia. The widely used thiopurines are responsible for a number of common adverse events, only some of which can be explained by genetic polymorphisms in thiopurine S-methyltransferase. The recent literature has implicated another enzyme, inosine triphosphate pyrophosphatase (ITPA), in the adverse drug reaction of thiopurines. However, the evidence for a correlation between ITPA deficiency and adverse events is conflicting. Most of the previous studies rely on genotyping methods and there are very few phenotyping methods published for the determination of ITPA activity [1]. Here, we report the validation of a weak anion exchange high-performance liquid chromatography method to determine ITPA activity in red blood cells and to investigate the relationship with the occurrence of adverse events during azathioprine therapy [2–3]. Material and methods: ITPA activity was assessed by the enzymatic conversion of inosine triphosphate (ITP) to inosine monophosphate (IMP). IMP, inosine diphosphate (IDP), and ITP were analysed on a Luna NH2 column, a weak anion exchange phase that exhibits both ionic and hydrophobic properties. Results: The chromatographic method reported allows the analysis of IMP, IDP and ITP in a single run of 14 min. The method was linear in the range 5– 3000 lmole/L (r²>0.998). Intraassay and interassay precisions were below 10% for red blood cells supplemented with 25, 750 and 1250 lmole/L IMP and interassay precision was 7.7% for a lysat control with a mean ITPA activity of 54.8 lmole/g Hb/h. The quantification limit was 5 lmol/L with a CV = 8.0%. The frequency distribution of ITPase from 321 Caucasian patients was investigated. Discussion / Conclusion: This method has potential to provide further information on the interest of ITPA phenotyping through its use in large scale studies. In addition, it can be easily applied in the clinical setting if routine ITPA phenotyping is proven to be of clinical importance. References: [1] Shipkova M, Lorenz K, Oellerich M, et al. Clin Chem. 2006;52(2):240–247. [2] Citterio-Quentin A, Salvi JP, Boulieu R. Ther Drug Monit. 2012;34(4):477– 480. [3] Citterio-Quentin A, Long S, Salvi JP, Moulsma M, Boulieu R. Ther Drug Monit. 2014;36(5):689–691.
with ST
without ST
P
Dose (mg/kg/day)
0.12
0.11
75 year-old) is a frequent disease in which antithrombotics have demonstrated significant benefits in preventing venous or arterial thrombotic events. Oral vitamine K antagonist (VKA) are widely used in this indication but iatrogenic side effects are limiting their use in the elderly and some general practitioners (GPs) prefer to prescribe antiplatelet agents (APA). European and US guidelines currently recommend oral anticoagulants over antiplatelet agents for stroke prevention in AF, that is why new oral anticoagulants (NOAC) will modify the prescription practice. The objective of this study was to assess the current practice of GPs to treat FA in elderly patients in Brittany, in the context of the recent NOAC availability. Material and methods: A self-administering form had been sent to 621 GPs from January 2012 to March 2012. Demographic data and data about prescription profile of VKA, APA and NOAC in the elderly were collected. Results: Response rate was 51%. Seventy-two per cent of GPs prescribed APA in their elderly patients with FA and 51% thought to switch for a NOAC. Fluindione was the VKA of choice, instead of coumadine. In well-controlled patients with VKA, only 14% of GPs did consider a systematic switching to NOAC. However, in patients with fluctuating international normalized ratio (INR) on VKA, 89% of GPs considered a NOAC prescription. Discussion / Conclusion: International guidelines are not followed by GPs for elderly patients with FA, with numerous APA prescriptions. Despite clinical evidence of efficacy of coumadine, fluindione was the VKA of choice. A switch VKA / NOAC was almost systematically considered in patients with fluctuating INR. PM2-053 Surveillance of waiting times for access to treatment: a registry-based computed approach in breast cancer A Quilleta, G Defossezb, P Ingrandc aCRPV Poitiers – Poitiers (France); bRegistre general des cancers de Poitou-Charentes – Poitiers (France); cRegistre general des cancers de Poitou-Charentes, INSERM – CIC 1402 – Poitiers (France) Introduction: Controlling waiting times to access breast cancer treatment is a health policy priority in many countries. The aim of this study was to evaluate an original method to produce waiting times indicators of access to treatments, and to analyse their determinants in non-metastatic breast cancer patients using a computer algorithm applied to data routinely integrated by a population cancer registry. Material and methods: We studied a sample of 974 women from the PoitouCharentes regional cancer registry aged 85 years or younger, diagnosed with stages I to III breast adenocarcinoma between 2008 and 2010. Waiting times were automatically computed from an algorithm modelling the care trajectory and then compared with national guidelines. Results: In patients treated with adjuvant chemotherapy, the waiting times between surgery and chemotherapy (SC) and between surgery and radiotherapy
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(SCR) were consistent with the guidelines in 52.4% and 56.3% of cases, respectively. In patients untreated with adjuvant chemotherapy, the waiting times between surgery and radiotherapy (SR) were consistent with the guidelines in 89.2% of cases. Younger age, a higher TNM stage, a lower SBR grade, having a triple negative tumour, attending multidisciplinary meetings, being a patient at a public hospital, having an additional biopsy and secondary surgical revision were associated with increased waiting times. Significant heterogeneity of waiting times between geographical areas of treatment was found for every waiting time studied. Discussion / Conclusion: The original use, in this context, of a registry-based automated algorithm to generate waiting times will help to follow these indicators routinely and more efficiently while also identifying associated medical, organisational and temporal determinants. PM2-054 Lichen planopilaris due to dasatinib: a case report B Revol, M Lepelley, C Villier CRPV – Grenoble (France) Introduction: Cutaneous reactions are the most common non hematologic side effect of tyrosine kinase inhibitors (TKIs). Several cases of lichenoid eruption on the skin or oral mucosa have been described with imatinib, first in class drug approved for chronic myeloid leukemia [1–4]. To our knowledge, no lichenoid reaction has been reported with dasatinib or nilotinib, second-generation TKIs. Material and methods: We report the case of a 34-year-old female with lichen planopilaris, probably due to the use of dasatinib. Results: Chronic myeloid leukemia was discovered in November 2010 and dasatinib introduced in September 2012. Following the increase of the dose to 140 mg/day in July 2013, the patient observed the appearance of five bald patches on the scalp. On cutaneous examination: perifollicular erythema and keratotic plugs were observed, suggestive of lichen planopilaris. In November 2013 skin biopsy found a pseudo-comedonal keratin accumulation around hair follicles, surrounded by a chronic inflammatory infiltrate. PAS staining is negative. The histological appearance is therefore compatible with the diagnosis of lichen planopilaris. Daily topical clobetasol is prescribed. After three weeks, the patches are no longer inflammatory. In February 2014, given the transcript levels of bcrabl, major molecular response to dasatinib after 18 months is not reached. In this context, the occurrence of lichen planopilaris resulted in the discontinuation of dasatinib. The hair loss improved one month later. Discussion / Conclusion: This case report suggests that lichenoid reactions are not only observed with imatinib, but a class-effect of TKIs. The mechanisms behind cutaneous eruptions associated with TKIs remain unknown. The altered expression of c-kit may induce epidermal inflammation and other changes in epidermal homeostasis [5]. References: [1] Lim D. et al. Oral lichenoid reaction to imatinib (STI 571, Gleevec). Dermatology 2002; 205: 169–171. [2] Dalmau J. et al. Imatinib-associated lichenoid eruption: acitretin treatment allows maintained antineoplastic effect. Br J Dermatol 2006; 154: 1199– 1219. [3] Chan C.Y.S. et al. Cutaneous lichenoid dermatitis associated with imatinib mesylate. Dermatol Online J 2007; 13: 29. [4] Basso F.G. et al. Skin and oral lesions associated to imatinib mesylate therapy. Support Care Cancer 2009; 17: 45–48. [5] Deguchi N. et al. Imatinib mesylate causes palmoplantar hyperkeratosis and nail dystrophy in three patients with chronic myeloid leukemia. Br J Dermatol 2006; 143: 1216–1217.
© 2015 The Authors. Fundamental and Clinical Pharmacology © 2015 Societe Francßaise de Pharmacologie et de Therapeutique 29 (Suppl. 1), 34–46
